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Inhibition of platelet-derived growth factor-AB signaling prevents electromechanical remodeling of adult atrial myocytes that contact myofibroblasts.

ABSTRACT: Persistent atrial fibrillation (PAF) results in electromechanical and structural remodeling by mechanisms that are poorly understood. Myofibroblast proliferation and fibrosis are major sources of structural remodeling in PAF. Myofibroblasts also interact with atrial myocytes via direct physical contact and release of signaling molecules, which may contribute to remodeling.To determine whether myofibroblasts contribute to atrial myocyte electromechanical remodeling via direct physical contact and platelet-derived growth factor (PDGF) signaling.Myofibroblasts and myocytes from adult sheep atria were co-cultured for 24 hours. Alternatively adult sheep atrial myocytes were exposed to 1 ng/mL recombitant PDGF AB peptide for 24 hours.Myocytes making contact with myofibroblasts demonstrated significant reduction (P ? .05) in peak L-type calcium current density, shortening of action potential duration (APD), and reduction in calcium transients. These effects were blocked by pretreatment with a PDGF-AB neutralizing anti-body. Heterocellular contact also severely disturbed the localization of the L-type calcium channel. Myocytes exposed to recombinant PDGF-AB peptide for 24 hours demonstrated reduced APD50, APD80 and Peak L-type calcium current. Pretreatment with a PDGF-AB neutralizing antibody prevented these effects. Finally, while control atrial myocytes did not respond in a 1:1 manner to pacing frequencies of 3 Hz or higher, atrial myocytes from hearts that were tachypaced for 2 months and normal myocytes treated with PDGF-AB for 24 hours could be paced up to 10 Hz.In addition to leading to fibrosis, atrial myofibroblasts contribute to electromechanical remodeling of myocytes via direct physical contact and release of PDGF-AB, which may be a factor in PAF-induced remodeling.

SUBMITTER: Musa H

PROVIDER: S-EPMC3692578 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Inhibition of platelet-derived growth factor-AB signaling prevents electromechanical remodeling of adult atrial myocytes that contact myofibroblasts.

Musa Hassan H Kaur Kuljeet K O'Connell Ryan R Klos Matt M Guerrero-Serna Guadalupe G Avula Uma Mahesh R UM Herron Todd J TJ Kalifa Jerômé J Anumonwo Justus M B JM Jalife José J

Heart rhythm 20130314 7

<h4>Background</h4>Persistent atrial fibrillation (PAF) results in electromechanical and structural remodeling by mechanisms that are poorly understood. Myofibroblast proliferation and fibrosis are major sources of structural remodeling in PAF. Myofibroblasts also interact with atrial myocytes via direct physical contact and release of signaling molecules, which may contribute to remodeling.<h4>Objective</h4>To determine whether myofibroblasts contribute to atrial myocyte electromechanical remod ...[more]

PMID: 23499624

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Project description:BackgroundModerate intensity exercise is associated with a decreased incidence of atrial fibrillation. However, extensive training in competitive athletes is associated with an increased atrial fibrillation risk. We evaluated the effects of 24 months of high intensity exercise training on left atrial (LA) mechanical and electric remodeling in sedentary, healthy middle-aged adults.MethodsSixty-one participants (53±5 years) were randomized to 10 months of exercise training followed by 14 months of maintenance exercise or stretching/balance control. Fourteen Masters athletes were added for comparison. Left ventricular (LV) and LA volumes underwent 3D echocardiographic assessment, and signal-averaged electrocardiographs for filtered P-wave duration and atrial late potentials were completed at 0, 10, and 24 months. Extended ambulatory monitoring was performed at 0 and 24 months. Within and between group differences from baseline were compared using mixed-effects model repeated-measures analysis.ResultsFifty-three participants completed the study (25 control, 28 exercise) with 88±11% adherence to assigned exercise sessions. In the exercise group, both LA and LV end diastolic volumes increased proportionately (19% and 17%, respectively) after 10 months of training (peak training load). However, only LA volumes continued to increase with an additional 14 months of exercise training (LA volumes 55%; LV end diastolic volumes 15% at 24 months versus baseline; P<0.0001 for all). The LA:LV end diastolic volumes ratio did not change from baseline to 10 months, but increased 31% from baseline in the Ex group ( P<0.0001) at 24 months, without a change in controls. There were no between group differences in the LA ejection fraction, filtered P-wave duration, atrial late potentials, and premature atrial contraction burden at 24 months and no atrial fibrillation was detected. Compared with Masters athletes, the exercise group demonstrated lower absolute LA and LV volumes, but had a similar LA:LV ratio after 24 months of training.ConclusionsTwenty-four months of high intensity exercise training resulted in LA greater than LV mechanical remodeling with no observed electric remodeling. Together, these data suggest different thresholds for electrophysiological and mechanical changes may exist in response to exercise training, and provide evidence supporting a potential mechanism by which high intensity exercise training leads to atrial fibrillation.Clinical trial registrationURL: https://www.clinicaltrials.gov . Unique identifier: NCT02039154.

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Inhibition of platelet-derived growth factor-AB signaling prevents electromechanical remodeling of adult atrial myocytes that contact myofibroblasts.

Publications

Inhibition of platelet-derived growth factor-AB signaling prevents electromechanical remodeling of adult atrial myocytes that contact myofibroblasts.

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